Immuno-Modulation of Hematopoietic Stem and Progenitor Cells in Inflammation

Abstract

Lifelong blood production is maintained by bone marrow (BM)-residing hematopoietic stem cells (HSCs) that are defined by two special properties: multipotency and self-renewal. Since dysregulation of either may lead to a differentiation block or extensive proliferation causing dysplasia or neoplasia, the genomic integrity and cellular function of HSCs must be tightly controlled and preserved by cell-intrinsic programs and cell-extrinsic environmental factors of the BM. The BM had been long regarded an immune-privileged organ shielded from immune insults and inflammation, and was thereby assumed to provide HSCs and immune cells with a protective environment to ensure blood and immune homeostasis. Recently, accumulating evidence suggests that hemato-immune challenges such as autoimmunity, inflammation or infection elicit a broad spectrum of immunological reactions in the BM, and in turn, influence the function of HSCs and BM environmental cells. Moreover, in analogy with the emerging concept of "trained immunity", certain infection-associated stimuli are able to train HSCs and progenitors to produce mature immune cells with enhanced responsiveness to subsequent challenges, and in some cases, form an inflammatory or infectious memory in HSCs themselves. In this review, we will introduce recent findings on HSC and hematopoietic regulation upon exposure to various hemato-immune stimuli and discuss how these challenges can elicit either beneficial or detrimental outcomes on HSCs and the hemato-immune system, as well as their relevance to aging and hematologic malignancies.

Keywords: BM environment; hematopoietic stem cells; immune-memory; infection; inflammation.

Figure 1

Bacteria-induced activation of HSPCs. Steady-state hematopoiesis (upper): Hematopoietic stem and progenitor cells (HSPCs) self-renew and differentiate into myeloid progenitors (MPs) and common lymphoid progenitors (CLPs) to produce mature cells. The divisional manner of HSPCs toward either self-renewal or maturation (myelopoiesis/lymphopoiesis) is tightly controlled to sustain lifelong hematopoiesis. Hematopoiesis under infection (lower): Bacterial components reach the bone marrow (BM) via systemic blood circulation to activate pattern recognition receptors (PRRs) such as toll-like receptors (TLRs) expressed on HSPCs and promote their proliferation. Bacteria-associated molecules reach the BM and can alternatively activate TLRs and NOD1/2 on endothelial cells or mesenchymal stromal cells (MSCs), leading to the secretion of inflammatory cytokines such as G-CSF and IL-6. These secreted cytokines promote granulopoiesis by acting on HSPCs. Cytotoxic T lymphocytes (CTLs) respond to bacterial infection and produce inflammatory cytokines such as IFNs, which migrate to the BM and activate corresponding receptors expressed on HSPCs. This results in reduced HSPC self-renewal and enhanced myelopoiesis. Severe bacterial infection such as sepsis rapidly ablates osteoblasts and induces lymphopenia due to lack of osteoblast-derived IL-7. CX3CR1⁺ mononuclear cells (MNCs) sense bacteria-derived molecules such as bacterial DNA via endolysosomal TLRs and secrete the inflammatory cytokines, IL-1, IL-6, and TNF, which control the expansion of hematopoietic progenitors, and shift the hematopoietic program toward myelopoiesis. Taken together, bacterial challenges induce HSPC activation and myelopoiesis directly and indirectly at the expense of lymphopoiesis.

Figure 2

The concept of trained immunity in HSPCs and reported stressors for its induction. (A) A one-time exposure to an immunological challenge drives proliferation and differentiation of HSPCs to enhance host immunity. A primary challenge by innate immune insults such as BCG, β-glucan or a Western-type diet induces epigenetic or metabolic changes at the cellular level in HSPCs, and activates them directly via cell intrinsic changes or indirectly via cytokine production such as IL-1β and GM-CSF. A secondary challenge such as LPS re-stimulation enhances overall immune response, cytokine production and myelopoiesis (trained immunity). Due to memory formation, HSPCs respond better to a secondary challenge and produce more reactive immune cells that can exert robust immune responses against the infection. A hypothetical scheme of immune-tolerance is shown. Immune-tolerance induces immune suppression upon a secondary challenge, which impairs HSPC function and their potency to differentiate into myeloid cells. As a result, immune responses decline and renders the host more susceptible to infection. (B) The schematic figure summarizes findings published in previous reports and highlights the role of inflammation on trained HSPCs. Several types of inflammation-causing components including β-glucan, a Western-type diet and BCG affect HSPCs at the intracellular level. These factors induce metabolic and epigenetic changes such as enhanced glycolysis and cholesterol biosynthesis, histone modifications, changes in cell cycle state and an increase in DNA damage.